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Recent studies have evaluated the landscape of gene mutations in pediatric acute lymphoblastic leukemia (ALL) and have identified EPPK1 (HGNC:15577) as one of the recurrently mutated genes in this setting (PMID:35733807). In a cohort of 71 children with ALL, EPPK1 mutations were observed in approximately 9.8% of B-cell ALL cases, highlighting a potential role in glucocorticoid resistance. This observation was made alongside other genes of higher mutation frequency but without detailed variant level descriptions, as specific HGVS‐described changes were not provided. The lack of explicit segregation data (e.g., affected relatives) and absence of a defined variant spectrum limit the strength of the genetic evidence. No familial or functional segregation analysis was performed, which restricts the ability to definitively classify this association within a Mendelian inheritance framework. Overall, the genetic data for EPPK1 in pediatric ALL remains quantitatively modest and derived from a single study context.
Functional investigations addressing the mechanistic role of EPPK1 in mediating glucocorticoid resistance have not been reported, resulting in a limited experimental evidence base. Consequently, although the study detected an association between EPPK1 mutations and clinical features of ALL, no in vitro, in vivo, or rescue experiments were available to further support a pathogenic mechanism. The lack of corroborative functional data and segregation analysis confines the overall gene–disease association to a Limited level according to ClinGen guidelines. Additionally, no conflicting or alternative phenotypic evidence was reported that would either strengthen or refute the observed link. Future studies including detailed variant characterization and functional assessments are warranted to better establish the clinical utility of EPPK1 mutation testing in glucocorticoid resistance. Key take‐home: While EPPK1 mutations are observed in pediatric ALL, their current evidentiary support is limited, and further validation is necessary to inform diagnostic decision‑making and potential therapeutic strategies.
Gene–Disease AssociationLimitedThe association is based on a single study cohort of 71 probands (PMID:35733807) with a modest mutation frequency and no segregation analysis. Genetic EvidenceLimitedEPPK1 mutations were observed in approximately 9.8% of B-cell ALL cases without detailed variant or familial segregation data, limiting the genetic evidence. Functional EvidenceLimitedNo functional studies, model systems, or rescue experiments have been reported to substantiate a mechanistic role for EPPK1 in glucocorticoid resistance. |